Comparison of 68Ga-DOTANOC and 68Ga-DOTATATE PET/CT within patients with gastroenteropancreatic neuroendocrine tumors

Somatostatin receptor PET tracers such as [68Ga-DOTA,1-Nal3]-octreotide (68Ga-DOTANOC) and [68Ga-DOTA,Tyr3]-octreotate (68Ga-DOTATATE) have shown promising results in patients with neuroendocrine tumors, with a higher lesion detection rate than is achieved with 18F-fluorodihydroxyphenyl-l-alanine PET, somatostatin receptor SPECT, CT, or MR imaging. 68Ga-DOTANOC has high affinity for somatostatin receptor subtypes 2, 3, and 5 (sst2,3,5). It has a wider receptor binding profile than 68Ga-DOTATATE, which is sst2-selective. The wider receptor binding profile might be advantageous for imaging because neuroendocrine tumors express different subtypes of somatostatin receptors. The goal of this study was to prospectively compare 68Ga-DOTANOC and 68Ga-DOTATATE PET/CT in the same patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and to evaluate the clinical impact of 68Ga-DOTANOC PET/CT. Methods: Eighteen patients with biopsy-proven GEP-NETs were evaluated with 68Ga-DOTANOC and 68Ga-DOTATATE using a randomized crossover design. Labeling of DOTANOC and DOTATATE with 68Ga was standardized using a fully automated synthesis device. PET/CT findings were compared with 3-phase CT scans and in some patients with MR imaging, 18F-FDG PET/CT, and histology. Uptake in organs and tumor lesions was quantified and compared by calculation of maximum standardized uptake values (SUVmax) using volume computer-assisted reading. Results: Histology revealed low-grade GEP-NETs (G1) in 4 patients, intermediate grade (G2) in 7, and high grade (G3) in 7. 68Ga-DOTANOC and 68Ga-DOTATATE were false-negative in only 1 of 18 patients. In total, 248 lesions were confirmed by cross-sectional and PET imaging. The lesion-based sensitivity of 68Ga-DOTANOC PET was 93.5%, compared with 85.5% for 68Ga-DOTATATE PET (P = 0.005). The better performance of 68Ga-DOTANOC PET is attributed mainly to the significantly higher detection rate of liver metastases rather than tumor differentiation grade. Multivariate analysis revealed significantly higher SUVmax in G1 tumors than in G3 tumors (P = 0.009). This finding was less pronounced with 68Ga-DOTANOC (P > 0.001). Altogether, 68Ga-DOTANOC changed treatment in 3 of 18 patients (17%). Conclusion: The sst2,3,5-specific radiotracer 68Ga-DOTANOC detected significantly more lesions than the sst2-specific radiotracer 68Ga-DOTATATE in our patients with GEP-NETs. The clinical relevance of this finding has to be proven in larger studies.

Plasma DNA is Elevated in Patients with Deep Vein Thrombosis

OBJECTIVE To investigate if plasma DNA is elevated in patients with deep vein thrombosis (DVT) and to determine whether there is a correlation with other biomarkers of DVT. BACKGROUND Leukocytes release DNA to form extracellular traps (ETs), which have recently been linked to experimental DVT. In baboons and mice, extracellular DNA co-localized with von Willebrand factor (VWF) in the thrombus and DNA appeared in circulation at the time of thrombus formation. ETs have not been associated with clinical DVT. SETTING From December 2008 to August 2010, patients were screened through the University of Michigan Diagnostic Vascular Unit and were divided into three distinct groups: 1) the DVT positive group, consisting of patients who were symptomatic for DVT, which was confirmed by compression duplex ultrasound (n=47); 2) the DVT negative group, consisting of patients that present with swelling and leg pain but had a negative compression duplex ultrasound, (n=28); and 3) a control group of healthy non-pregnant volunteers without signs or symptoms of active or previous DVT (n=19). Patients were excluded if they were less than 18 years of age, unwillingness to consent, pregnant, on an anticoagulant therapy, or diagnosed with isolated calf vein thrombosis. METHODS Blood was collected for circulating DNA, CRP, D-dimer, VWF activity, myeloperoxidase (MPO), ADAMTS13 and VWF. The Wells score for a patient's risk of DVT was assessed. The Receiver Operating Characteristic (ROC) curve was generated to determine the strength of the relationship between circulating DNA levels and the presence of DVT. A Spearman correlation was performed to determine the relationship between the DNA levels and the biomarkers and the Wells score. Additionally the ratio of ADAMTS13/VWF was assessed. RESULTS Our results showed that circulating DNA (a surrogate marker for NETs) was significantly elevated in DVT patients, compared to both DVT negative patients (57.7±6.3 vs. 17.9±3.5ng/mL, P<.01) and controls (57.7±6.3 vs. 23.9±2.1ng/mL, P<.01). There was a strong positive correlation with CRP (P<.01), D-dimer (P<.01), VWF (P<.01), Wells score (P<.01) and myeloperoxidase (MPO) (P<.01), along with a strong negative correlation with ADAMTS13 (P<.01) and the ADAMTS13/VWF ratio. The logistic regression model showed a strong association between plasma DNA and the presence of DVT (ROC curve was determined to be 0.814). CONCLUSIONS Plasma DNA is elevated in patients with deep vein thrombosis and correlates with biomarkers of DVT. A strong correlation between circulating DNA and MPO suggests that neutrophils may be a source of plasma DNA in patients with DVT.

A prospective cohort study evaluating the state of medical readiness in the United States Air Force and risk factors to improve the medical readiness posture

A cohort of 418 United States Air Force (USAF) personnel from over 15 different bases deployed to Morocco in 1994. This was the first study of its kind and was designed with two primary goals: to determine if the USAF was medically prepared to deploy with its changing mission in the new world order, and to evaluate factors that might improve or degrade USAF medical readiness. The mean length of deployment was 21 days. The cohort was 95% male, 86% enlisted, 65% married, and 78% white.^ This study shows major deficiencies indicating the USAF medical readiness posture has not fully responded to meet its new mission requirements. Lack of required logistical items (e.g., mosquito nets, rainboots, DEET insecticide cream, etc.) revealed a low state of preparedness. The most notable deficiency was that 82.5% (95% CI = 78.4, 85.9) did not have permethrin pretreated mosquito nets and 81.0% (95% CI = 76.8, 84.6) lacked mosquito net poles. Additionally, 18% were deficient on vaccinations and 36% had not received a tuberculin skin test. Excluding injections, the overall compliance for preventive medicine requirements had a mean frequency of only 50.6% (95% CI = 45.36, 55.90).^ Several factors had a positive impact on compliance with logistical requirements. The most prominent was "receiving a medical intelligence briefing" from the USAF Public Health. After adjustment for mobility and age, individuals who underwent a briefing were 17.2 (95% CI = 4.37, 67.99) times more likely to have received an immunoglobulin shot and 4.2 (95% CI = 1.84, 9.45) times more likely to start their antimalarial prophylaxsis at the proper time. "Personnel on mobility" had the second strongest positive effect on medical readiness. When mobility and briefing were included in models, "personnel on mobility" were 2.6 (95% CI = 1.19, 5.53) times as likely to have DEET insecticide and 2.2 (95% CI = 1.16, 4.16) times as likely to have had a TB skin test.^ Five recommendations to improve the medical readiness of the USAF were outlined: upgrade base level logistical support, improve medical intelligence messages, include medical requirements on travel orders, place more personnel on mobility or only deploy personnel on mobility, and conduct research dedicated to capitalize on the powerful effect from predeployment briefings.^ Since this is the first study of its kind, more studies should be performed in different geographic theaters to assess medical readiness and establish acceptable compliance levels for the USAF. ^

Within-Season Homing Movements of Displaced Mature Sunapee Trout (Salvelinus Alpinus) in Floods Pond, Maine

Tagging, displacemenat nd recapture, and ultrasonict racking of displaced mature Sunapee trout (Salvelinusa Ipinus) in Floods Pond, Maine, demonstrated that rapid within-season homing occurs in this relict form of Arctic char. Of the trout displaced about 1.8 km from their spawning ground from 1972 to 1975, 9% to 32% were recaptured one to four times within the same spawning season in trap nets set on the spawning ground. Eight of 14 trout tracked ultrasonically in 1975 homed in 2.5 to 10.0 h. Movements of the homing fish were variable; some trout homed paralleling the shoreline, others homed in open water or used a combination of near-shore and open-water movements. Behavior was similar between the sexes and during day and night, although two fish did begin to move just at sundown. Swimming speeds ranged from 15 to 35 cm s- 1 and averaged about 0 .6 body lengths s -1•. Swimming directions were not influenced by wind and wave direction, nor were swimming speeds within individual tracks influenced by cloud cover, wave height, or water depth. Heavy overcast at night m&y have inhibited movement. Sunapee trout are apparently familiar with the entire lake and travel widely within it. Visual features are postulated as orientational cues, though use of such cues is not clearly demonstrated by our experiments.

Homogeneous reprocessing of GPS, GLONASS and SLR observations

The International GNSS Service (IGS) provides operational products for the GPS and GLONASS constellation. Homogeneously processed time series of parameters from the IGS are only available for GPS. Reprocessed GLONASS series are provided only by individual Analysis Centers (i. e. CODE and ESA), making it difficult to fully include the GLONASS system into a rigorous GNSS analysis. In view of the increasing number of active GLONASS satellites and a steadily growing number of GPS+GLONASS-tracking stations available over the past few years, Technische Universität Dresden, Technische Universität München, Universität Bern and Eidgenössische Technische Hochschule Zürich performed a combined reprocessing of GPS and GLONASS observations. Also, SLR observations to GPS and GLONASS are included in this reprocessing effort. Here, we show only SLR results from a GNSS orbit validation. In total, 18 years of data (1994–2011) have been processed from altogether 340 GNSS and 70 SLR stations. The use of GLONASS observations in addition to GPS has no impact on the estimated linear terrestrial reference frame parameters. However, daily station positions show an RMS reduction of 0.3 mm on average for the height component when additional GLONASS observations can be used for the time series determination. Analyzing satellite orbit overlaps, the rigorous combination of GPS and GLONASS neither improves nor degrades the GPS orbit precision. For GLONASS, however, the quality of the microwave-derived GLONASS orbits improves due to the combination. These findings are confirmed using independent SLR observations for a GNSS orbit validation. In comparison to previous studies, mean SLR biases for satellites GPS-35 and GPS-36 could be reduced in magnitude from −35 and −38 mm to −12 and −13 mm, respectively. Our results show that remaining SLR biases depend on the satellite type and the use of coated or uncoated retro-reflectors. For Earth rotation parameters, the increasing number of GLONASS satellites and tracking stations over the past few years leads to differences between GPS-only and GPS+GLONASS combined solutions which are most pronounced in the pole rate estimates with maximum 0.2 mas/day in magnitude. At the same time, the difference between GLONASS-only and combined solutions decreases. Derived GNSS orbits are used to estimate combined GPS+GLONASS satellite clocks, with first results presented in this paper. Phase observation residuals from a precise point positioning are at the level of 2 mm and particularly reveal poorly modeled yaw maneuver periods.

Contribution of Starlette, Stella, and AJISAI to the SLR-derived global reference frame

The contribution of Starlette, Stella, and AJI-SAI is currently neglected when defining the International Terrestrial Reference Frame, despite a long time series of precise SLR observations and a huge amount of available data. The inferior accuracy of the orbits of low orbiting geodetic satellites is the main reason for this neglect. The Analysis Centers of the International Laser Ranging Service (ILRS ACs) do, however, consider including low orbiting geodetic satellites for deriving the standard ILRS products based on LAGEOS and Etalon satellites, instead of the sparsely observed, and thus, virtually negligible Etalons. We process ten years of SLR observations to Starlette, Stella, AJISAI, and LAGEOS and we assess the impact of these Low Earth Orbiting (LEO) SLR satellites on the SLR-derived parameters. We study different orbit parameterizations, in particular different arc lengths and the impact of pseudo-stochastic pulses and dynamical orbit parameters on the quality of the solutions. We found that the repeatability of the East and North components of station coordinates, the quality of polar coordinates, and the scale estimates of the reference are improved when combining LAGEOS with low orbiting SLR satellites. In the multi-SLR solutions, the scale and the Z component of geocenter coordinates are less affected by deficiencies in solar radiation pressure modeling than in the LAGEOS-1/2 solutions, due to substantially reduced correlations between the Z geocenter coordinate and empirical orbit parameters. Eventually, we found that the standard values of Center-of-mass corrections (CoM) for geodetic LEO satellites are not valid for the currently operating SLR systems. The variations of station-dependent differential range biases reach 52 and 25 mm for AJISAI and Starlette/Stella, respectively, which is why estimating station dependent range biases or using station-dependent CoM, instead of one value for all SLR stations, is strongly recommended.This clearly indicates that the ILRS effort to produce CoM corrections for each satellite, which are site-specific and depend on the system characteristics at the time of tracking,is very important and needs to be implemented in the SLR data analysis.

Measurement of the neutrino velocity with the OPERA detector in the CNGS beam using the 2012 dedicated data

In spring 2012 CERN provided two weeks of a short bunch proton beam dedicated to the neutrino velocity measurement over a distance of 730 km. The OPERA neutrino experiment at the underground Gran Sasso Laboratory used an upgraded setup compared to the 2011 measurements, improving the measurement time accuracy. An independent timing system based on the Resistive Plate Chambers was exploited providing a time accuracy of ∼1 ns. Neutrino and anti-neutrino contributions were separated using the information provided by the OPERA magnetic spectrometers. The new analysis profited from the precision geodesy measurements of the neutrino baseline and of the CNGS/LNGS clock synchronization. The neutrino arrival time with respect to the one computed assuming the speed of light in vacuum is found to be δtν≡TOFc−TOFν=(0.6±0.4 (stat.)±3.0 (syst.)) ns and δtν¯≡TOFc−TOFν¯=(1.7±1.4 (stat.)±3.1 (syst.)) ns for νμ and ν¯μ, respectively. This corresponds to a limit on the muon neutrino velocity with respect to the speed of light of −1.8×10−6<(vν−c)/c<2.3×10−6 at 90% C.L. This new measurement confirms with higher accuracy the revised OPERA result.

The search for the primary tumor in metastasized gastroenteropancreatic neuroendocrine neoplasm.

Gastroenteropancreatic neuroendocrine tumors (NETs) often present as liver metastasis from a carcinoma of unknown primary. We recently showed that primary NETs from the pancreas, small intestine and stomach as well as their respective liver metastases differ from each other by the expression profile of the three genes CD302, PPWD1 and ABHB14B. The gene and protein expression of CD302, PPWD1, and ABHB14B was studied in abdominal NET metastases to identify the site of the respective primary tumors. Cryopreserved tissue from NET metastases collected in different institutions (group A: 29, group B: 50, group C: 132 specimens) were examined by comparative genomic hybridization (Agilent 105 K), gene expression analysis (Agilent 44 K) (groups A and B) and immunohistochemistry (group C). The data were blindly evaluated, i.e. without knowing the site of the primary. Gene expression analysis correctly revealed the primary in the ileum in 94 % of the cases of group A and in 58 % of group B. A pancreatic primary was predicted in 83 % (group A) and 20 % (group B), respectively. The combined sensitivity of group A and B was 75 % for ileal NETs and 38 % for pancreatic NETs. Immunohistochemical analysis of group C revealed an overall sensitivity of 80 %. Gene and protein expression analysis of CD302 and PPWD1 in NET metastases correctly identifies the primary in the pancreas or the ileum in 80 % of the cases, provided that the tissue is well preserved. Immunohistochemical profiling revealed CD302 as the best marker for ileal and PPWD1 for pancreatic detection.

Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies.

BACKGROUND Acute thrombotic microangiopathies (TMAs) are characterized by excessive microvascular thrombosis and are associated with markers of neutrophil extracellular traps (NETs) in plasma. NETs are composed of DNA fibers and promote thrombus formation through the activation of platelets and clotting factors. OBJECTIVE The efficient removal of NETs may be required to prevent excessive thrombosis such as in TMAs. To test this hypothesis, we investigated whether TMAs are associated with a defect in the degradation of NETs. APPROACH AND RESULTS We show that NETs generated in vitro were efficiently degraded by plasma from healthy donors. However, NETs remained stable after exposure to plasma from TMA patients. The inability to degrade NETs was linked to a reduced DNase activity in TMA plasma. Plasma DNase1 was required for efficient NET-degradation and TMA plasma showed decreased levels of this enzyme. Supplementation of TMA plasma with recombinant human DNase1 restored NET-degradation activity. CONCLUSIONS Our data indicates that DNase1-mediated degradation of NETs is impaired in patients with TMAs. The role of plasma DNases in thrombosis is, as of yet, poorly understood. Reduced plasma DNase1 activity may cause the persistence of pro-thrombotic NETs and thus promote microvascular thrombosis in TMA patients. This article is protected by copyright. All rights reserved.

The Glucose-Dependent Insulinotropic Polypeptide Receptor: A Novel Target for Neuroendocrine Tumor Imaging-First Preclinical Studies

A new family of peptide receptors, the incretin receptor family, overexpressed on many neuroendocrine tumors (NETs) is of great importance because it may enable the in vivo peptide-based receptor targeting of a category of NETs that does not express the somatostatin receptor. Impressive in vivo diagnostic data were published for glucagonlike peptide 1 receptor-targeting radiopeptides. Recently, promising in vitro data have appeared for the second member of the incretin family, the glucose-dependent insulinotropic polypeptide (GIP) receptor. This prompted us to develop and evaluate a new class of radioligands with the potential to be used for the in vivo targeting of GIP receptor-positive tumors. METHODS GIP(1-42) was modified C-terminally, and the truncated peptides [Lys(30)(aminohexanoic acid [Ahx]-DOTA)]GIP(1-30)NH2 (EG1), [Lys(16)(Ahx-DOTA)]GIP(1-30)NH2 (EG2), and [Nle(14), Lys(30)(Ahx-DOTA)]GIP(1-30)NH2 (EG4) were conjugated with Ahx-DOTA via the Lys(16) and Lys(30) side chains. Their inhibitory concentration of 50% (IC50) was determined using [(125)I-Tyr(10)]GIP(1-30) as radioligand and GIP(1-30) as control peptide. The DOTA conjugates were labeled with (111)In and (68)Ga. In vitro evaluation included saturation and internalization studies using the pancreatic endocrine cell line INR1G9 transfected with the human GIP receptor (INR1G9-hGIPr). The in vivo evaluation consisted of biodistribution and PET imaging studies on nude mice bearing INR1G9-hGIPr tumors. RESULTS Binding studies (IC50 and saturation studies) showed high affinity toward GIP receptor for the GIP conjugates. Specific in vitro internalization was found, and almost the entire cell-associated activity was internalized (>90% of the cell-bound activity), supporting the agonist potency of the (111)In-vectors. (111)In-EG4 and (68)Ga-EG4 were shown to specifically target INR1G9-hGIPr xenografts, with tumor uptake of 10.4% ± 2.2% and 17.0% ± 4.4% injected activity/g, 1 h after injection, respectively. Kidneys showed the highest uptake, which could be reduced by approximately 40%-50% with a modified-fluid-gelatin plasma substitute or an inhibitor of the serine protease dipeptidyl peptidase 4. The PET images clearly visualized the tumor. CONCLUSION The evaluation of EG4 as a proof-of-principle radioligand indicated the feasibility of imaging GIP receptor-positive tumors. These results prompt us to continue the development of this family of radioligands for imaging of a broad spectrum of NETs.

Comparison of GOCE-GPS gravity fields derived by different approaches

Several techniques have been proposed to exploit GNSS-derived kinematic orbit information for the determination of long-wavelength gravity field features. These methods include the (i) celestial mechanics approach, (ii) short-arc approach, (iii) point-wise acceleration approach, (iv) averaged acceleration approach, and (v) energy balance approach. Although there is a general consensus that—except for energy balance—these methods theoretically provide equivalent results, real data gravity field solutions from kinematic orbit analysis have never been evaluated against each other within a consistent data processing environment. This contribution strives to close this gap. Target consistency criteria for our study are the input data sets, period of investigation, spherical harmonic resolution, a priori gravity field information, etc. We compare GOCE gravity field estimates based on the aforementioned approaches as computed at the Graz University of Technology, the University of Bern, the University of Stuttgart/Austrian Academy of Sciences, and by RHEA Systems for the European Space Agency. The involved research groups complied with most of the consistency criterions. Deviations only occur where technical unfeasibility exists. Performance measures include formal errors, differences with respect to a state-of-the-art GRACE gravity field, (cumulative) geoid height differences, and SLR residuals from precise orbit determination of geodetic satellites. We found that for the approaches (i) to (iv), the cumulative geoid height differences at spherical harmonic degree 100 differ by only ≈10 % ; in the absence of the polar data gap, SLR residuals agree by ≈96 % . From our investigations, we conclude that real data analysis results are in agreement with the theoretical considerations concerning the (relative) performance of the different approaches.

GOCE: assessment of GPS-only gravity field determination

The GOCE satellite was orbiting the Earth in a Sun-synchronous orbit at a very low altitude for more than 4 years. This low orbit and the availability of high-quality data make it worthwhile to assess the contribution of GOCE GPS data to the recovery of both the static and time-variable gravity fields. We use the kinematic positions of the official GOCE precise science orbit (PSO) product to perform gravity field determination using the Celestial Mechanics Approach. The generated gravity field solutions reveal severe systematic errors centered along the geomagnetic equator. Their size is significantly coupled with the ionospheric density and thus generally increasing over the mission period. The systematic errors may be traced back to the kinematic positions of the PSO product and eventually to the ionosphere-free GPS carrier phase observations used for orbit determination. As they cannot be explained by the current higher order ionospheric correction model recommended by the IERS Conventions 2010, an empirical approach is presented by discarding GPS data affected by large ionospheric changes. Such a measure yields a strong reduction of the systematic errors along the geomagnetic equator in the gravity field recovery, and only marginally reduces the set of useable kinematic positions by at maximum 6 % for severe ionosphere conditions. Eventually it is shown that GOCE gravity field solutions based on kinematic positions have a limited sensitivity to the largest annual signal related to land hydrology.

A comment on the article “A collinearity diagnosis of the GNSS geocenter determination” by P. Rebischung, Z. Altamimi, and T. Springer

Meindl et al. (Adv Space Res 51(7):1047–1064, 2013) showed that the geocenter z -component estimated from observations of global navigation satellite systems (GNSS) is strongly correlated to a particular parameter of the solar radiation pressure (SRP) model developed by Beutler et al. (Manuscr Geod 19:367–386, 1994). They analyzed the forces caused by SRP and the impact on the satellites’ orbits. The authors achieved their results using perturbation theory and celestial mechanics. Rebischung et al. (J Geod doi:10.1016/j.asr.2012.10.026, 2013) also deal with the geocenter determination with GNSS. The authors carried out a collinearity diagnosis of the associated parameter estimation problem. They conclude “without much exaggerating that current GNSS are insensitive to any component of geocenter motion”. They explain this inability by the high degree of collinearity of the geocenter coordinates mainly with satellite clock corrections. Based on these results and additional experiments, they state that the conclusions drawn by Meindl et al. (Adv Space Res 51(7):1047–1064, 2013) are questionable. We do not agree with these conclusions and present our arguments in this article. In the first part, we review and highlight the main characteristics of the studies performed by Meindl et al. (Adv Space Res 51(7):1047–1064, 2013) to show that the experiments are quite different from those performed by Rebischung et al. (J Geod doi:10.1016/j.asr.2012.10.026,2013) . In the second part, we show that normal equation (NEQ) systems are regular when estimating geocenter coordinates, implying that the covariance matrices associated with the NEQ systems may be used to assess the sensitivity to geocenter coordinates in a standard way. The sensitivity of GNSS to the components of the geocenter is discussed. Finally, we comment on the arguments raised by Rebischung et al. (J Geod doi:10.1016/j.asr.2012.10.026, 2013) against the results of Meindl et al. (Adv Space Res 51(7):1047–1064, 2013).

GOCE: precise orbit determination for the entire mission

The Gravity field and steady-state Ocean Circulation Explorer (GOCE) was the first Earth explorer core mission of the European Space Agency. It was launched on March 17, 2009 into a Sun-synchronous dusk-dawn orbit and re-entered into the Earth’s atmosphere on November 11, 2013. The satellite altitude was between 255 and 225 km for the measurement phases. The European GOCE Gravity consortium is responsible for the Level 1b to Level 2 data processing in the frame of the GOCE High-level processing facility (HPF). The Precise Science Orbit (PSO) is one Level 2 product, which was produced under the responsibility of the Astronomical Institute of the University of Bern within the HPF. This PSO product has been continuously delivered during the entire mission. Regular checks guaranteed a high consistency and quality of the orbits. A correlation between solar activity, GPS data availability and quality of the orbits was found. The accuracy of the kinematic orbit primarily suffers from this. Improvements in modeling the range corrections at the retro-reflector array for the SLR measurements were made and implemented in the independent SLR validation for the GOCE PSO products. The satellite laser ranging (SLR) validation finally states an orbit accuracy of 2.42 cm for the kinematic and 1.84 cm for the reduced-dynamic orbits over the entire mission. The common-mode accelerations from the GOCE gradiometer were not used for the official PSO product, but in addition to the operational HPF work a study was performed to investigate to which extent common-mode accelerations improve the reduced-dynamic orbit determination results. The accelerometer data may be used to derive realistic constraints for the empirical accelerations estimated for the reduced-dynamic orbit determination, which already improves the orbit quality. On top of that the accelerometer data may further improve the orbit quality if realistic constraints and state-of-the-art background models such as gravity field and ocean tide models are used for the reduced-dynamic orbit determination.